Pyrrolo {2,1-b}{1,3}benzothiazepines with atypical antipsychotic activity

ABSTRACT

Polycondensated heterocycles with a pyrrole[2,1-b][1,3]benzothiazepine structure of the following formula (I)  
                 
 
     where the groups are defined as in the description are disclosed. As compared to known antipsychotic agents, these compounds present substantial activity associated with a simultaneous reduction in unwanted extrapyramidal symptoms. These compounds can be formulated in pharmaceutical compositions for the treatment of psychoses such as, for example, schizophrenia.

[0001] The present invention relates to the field of antipsychoticdrugs, in particular to polycondensated heterocycles with a pyrrolo[2,1-b][1,3]benzothiazepine structure.

STATE OF THE ART

[0002] The intervention of dopamine and dopaminergic neurons in thepathology of a variety of psychiatric and neurological disorders hasbeen amply documented (Caine, D. B., Therapeutics and Neurology;Blackwell Scientific Publications, Oxford 1980, p. 281). In addition, itis also known that drugs which are active on dopamine receptors may playan important role in the therapy of such disorders; there is thereforeconsiderable interest in the effects of dopamine agonist and antagonistcompounds on dopaminergic is receptors, particularly with a view totheir therapeutic implications.

[0003] Chlorpromazine and aloperidol have long been the treatment ofchoice for acute and chronic schizophrenia. It has been postulated thatthese drugs relieve the positive symptoms of the disease by blockingdopaminergic transmission in certain areas of the brain. Chlorpromazineand aloperidol are defined as “typical neuroleptic agents”: their actionis characterised by remission of the symptoms of schizophrenia,accompanied, however, by unwanted extrapyramidal collateral symptoms(motor disorders, catalepsy, hyperprolactinaemia, etc.). The eliminationof these adverse effects therefore constitutes an important objective inthe development of new neuroleptic therapies.

[0004] Clinical trials have demonstrated that not only dopamineantagonists but also 5-HT₂ antagonist compounds are capable of improvingthe symptoms of schizophrenia; in particular, it has been observed thatthe co-administration of 5-HT₂ antagonists and “typical” antipsychoticagents reduces the incidence of extrapyramidal symptoms as compared totreatment with neuroleptic agents alone (Psychopharmacol., 99, 1989,S18-S27; Niemegeers et al in 5-HT₂ Receptor Antagonists inSchizophrenia, Racagni Ed., Elsevier Publishers, 1991, Vol 1, pp.535-537).

[0005] Further developments in this sense have led to the generation ofdrugs with a mixed antagonist component, i.e. which are active ondifferent receptors.

[0006] Clozapine(8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine) isan antipsychotic agent capable of simultaneously antagonising dopamineon D₂ receptors and serotonin on 5-HT₂ receptors. This new actionprofile, called “atypical”, allows schizophrenia to be treated with alower incidence of extrapyramidal symptoms (J. Med. Chem., 39, 1996, pp.1172-1188).

[0007] Unfortunately, the occurrence of cases of agranulocytosis haslimited the therapeutic use of this drug (Lancet. 1975, 2, 657).

[0008] Octoclothepin(8-chloro-10-(4-methylpiperazino)-10,11-dihydrodibenzo[b,f]thiepin) is acompound partly endowed with “atypical” activity. Its pharmacologicalactivity has been studied in relation to the optical isomers of thiscompound (J. Med. Chem., 1991, 34, 2023-2030): a slightly greater effecton schizophrenia by the (S) form is unfortunately associated with agreater incidence of extrapyramidal effects, so that its use has beenwithdrawn from clinical trials. The (R) isomer presents a more“atypical” profile, with fewer side effects, but also an inferiorgeneral potency. Moreover, the two isomers prove to be endowed with thesame activity as 5-HT₂ and D₁ antagonists.

[0009] In view of the studies cited above, the need for antipsychoticagents with substantial therapeutic activity and without side effectsremains unsatisfied. In particular, the search continues forantipsychotic agents which present greater neuroleptic activity and alower incidence of extrapyramidal effects.

[0010] It has now surprisingly been found that polycondensatedheterocycles with a pyrrolo[2,1-b][1,3]benzothiazepine are endowed withan interesting pharmacological profile as antipsychotic activity.

ABSTRACT OF THE INVENTION

[0011] The present invention describes polycondensated heterocycles witha pyrrolo[2,]-b[1,3]benzothiazepine structure. As compared to knownantipsychotic agents, the compounds according to the invention presentsubstantial activity associated with a simultaneous reduction inunwanted extrapyramidal symptoms. The compounds object of the inventiondescribed herein can be formulated in pharmaceutical compositions forthe treatment of psychoses such as, for example, schizophrenia.

[0012] Accordingly, it is an object of the present inventionpolycondensated heterocycles with a pyrrolo[2,1-b][1,3]benzothiazepinestructure as disclosed in the formula (I) below.

[0013] Another object of the present invention is a process for thepreparation of said compounds.

[0014] Still another object of the present invention is the use of saidcompounds as medicaments, in particular as antipsychotic agents, for thetreatment of psychosis, such as schizophrenia, paranoid states,manic-depressive states, affective disorders, social withdrawal,personality regression, or hallucinations.

[0015] In its industrial aspects, the present invention providespharmaceutical compositions comprising at least a compound of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

[0016] The invention described herein relates to new derivatives with aneuroleptic action, corresponding to the following structural formula(I):

[0017] where:

[0018] R═H, Cl, Br, F, I, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkyl,C₅-C₆ cycloalkyl;

[0019] R₁=dialkylamine, 4-alkyl-1-piperazinyl,4-hydroxyalkyl-1-piperazinyl, 1-imidazolyl, 4-alkyl-1-piperidinyl

[0020] R₂=hydrogen, C₁-C₄ alkoxy, C₁-C₄ alkylthio; and thepharmaceutically acceptable salts thereof.

[0021] The formula (I) derivatives possess a chiral carbon atom inposition 9 on the benzothiazepine ring. The invention described hereincomprises both the formula (I) derivative in racemic form and the single(R) and (S) isomers, separately.

[0022] In formula (I), R preferably represents bromine, chlorine,fluorine or hydrogen, more preferably chlorine or fluorine; R₁ ispreferably a 4-methylpiperazinyl group; and R₂ preferably hydrogen.

[0023] Preferred derivatives according to the invention are theproducts:

[0024](±)-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine,hereinafter referred to as (±)-3a;

[0025](±)-7-chloro-9-(4-methylpiperazin-1-y)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine,hereinafter referred to as (±)-3b (ST1455);

[0026](+)-7-chloro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine,particularly preferred, hereinafter referred to as (+)-3b (ST1460)

[0027](±)-7-fluoro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine,hereinafter referred to as (3c) (ST1456);

[0028](±)-7-fluoro-9-(4-ethylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine(4c) (ST1457);

[0029](±)-7-fluoro-9-[4-(2′-hyroxyethylpiperazin-1-yl]-9,10-dihydropyrrolo[2,1b][1,3]benzothiazepine(5c) (ST1458);

[0030] The invention described herein also relates to new, effectivemethods of synthesis to obtain the newpyrrolo[2,1-b][1,3]benzothiazepine structures. One of the problemsencountered was that of realising a cyclisation method that made itpossible to obtain the particular formula (I) tricyclic system with highyields.

[0031] The various synthesis methods described herein include acyclisation reaction of a derivative comprising a phenyl group and apyrrole group, where the cyclisation leads to the formation of a [1,3]thiazepine ring. The result of said cyclisation reaction is preferably apyrrolobenzothiazepinone, which can be transformed into a formula (I)derivative by substituting the keto group on the thiazepine ring with agroup selected from the definitions given above for the radical R₁.

[0032] A process for the synthesis of formula (I) products isillustrated in Scheme 1A in its essential steps, and in Scheme 1B indetail.

[0033] With reference to Scheme 1B, the process involves the reaction of2-thiocyanate-pyrrole (11) with phenyl magnesium bromide to formthioether (12). Thioether (12), subjected to esterification andtransacylation reactions, gives rise to the derivative methylselenolate(15) comprising a phenyl group and a pyrrole group. Derivative (15) isthen subjected to a cyclisation reaction, with formation of product (9a)(pyrrolobenzothiazepinone). The cyclisation reaction is conducted in thepresence of a crystalline complex of triflate copper (I) and benzene.

[0034] Lastly, product (9a) is transformed into a formula (I) derivativeby means of subsequent modifications of the keto group on the thiazepinering to obtain derivatives with R₁ as described above.

[0035] One preferred process for the synthesis of formula (I) productsis illustrated in Scheme 2A in its essential steps and in Schemes 2B indetail.

[0036] With reference to Schemes 2B/1 and 2B/2, the process involves theformation of the intermediate product (21a,b,c. SCHEME 2B/1;bromophenylethanone; 21a: R═H; 21b: R═Cl; 21c=F). As far as theintermediate compound 21d is concerned, the synthetic path is outlinedin the Scheme C below.

[0037] The intermediate product (21a,b,c,d) is transformed into thecorresponding sulphoxide (23a,b,c,d). The latter, when subjected to acyclisation reaction, leads to the formation of the product (9a,b,c,d)(pyrrolobenzothiazepinone). The cyclisation reaction is conducted in thepresence of trifluoracetic anhydride and dimethylformamide.

[0038] This second synthesis method is preferred in that the cyclisationreaction and consequent formation of the thiazepine ring occur withdistinctly greater yields.

[0039] Products (9a), (9b), (9c) and (9d), obtained with the differentsynthesis methods described above are then transformed into a formula(I) derivative by substituting the keto group with a group selected fromthe definitions given above for the radical R₁.

[0040] It is then always possible to resolve the racemic products,however they are obtained, into the two active isomers by means offractionated crystallisation of the diastereoisomeric salts obtained bysalification with an optically active acid, such as tartaric acid,dibenzoyltartaric acid, camphoric acid, or camphor-sulphonic acid

[0041] A detailed description of the above-mentioned synthesis methodsis presented in the experimental part.

[0042] A further subject of the invention described herein consists inpharmaceutical compositions comprising formula (I) derivatives incombination with pharmacologically acceptable excipients and vehiclesand optionally with additional active ingredients which are useful inthe treatment of psychoses.

[0043] Examples of such optional active ingredients are thephenothiazines (e.g. chlorpromazine), the thiaxanthenes (e.g.chlorprothixene, titothixene), the butyrophenones (e.g. aloperidol), thedihydroindolones (e.g. molindone), the dibenzoxazepines (e.g. loxapine),the Rauwolfia alkaloids, etc.

[0044] Formula (I) compounds can be formulated in solid, liquid orsemisolid pharmaceutical forms. Examples of liquid formulations areinjectable solutions or solutions for oral use, syrups, elixirs,suspensions and emulsions. Examples of solid forms are tablets,capsules, microcapsules, powders and granulates.

[0045] Formula (I) compounds are endowed with a pronounced neurolepticand antipsychotic activity. This enables them to be used in theprevention and treatment of psychoses such as schizophrenia, paranoidstates, manic-depressive states, affective disorders, social withdrawal,personality regression, hallucinations, appetite disorders (anorexia)and related disorders. Additional indications may beanalgesia/anaesthesia, neuroleptic anaesthesia, anxiety manifestationsin the elderly, and extrapyramidal disturbances. The invention describedherein therefore includes the use of formula (I) products in thepreparation of medicinal products which are useful for the preventionand treatment of said disorders.

[0046] Some of the formula (I) products have an interesting D₃;D₁ ratio,indicating them useful in the treatment of the negative symptoms ofschizophrenia involving the emotional and cognitive spheres such as, forinstance, dementia.

[0047] As documented in the experimental part, the “atypicity” of theneuroleptic action of formula (I) derivatives makes it possible to treatthe above-mentioned pathologies effectively, at the same time reducingto a minimum the extrapyramidal side effects normally associated withthe classic antipsychotic agents. The substantial receptor activity thatcharacterises these compounds also makes it possible to considerablyreduce the dose necessary to achieve a therapeutic response, thusreducing toxicity and accumulation phenomena. The reduction of the dailydose is an aspect of particular interest in the treatment of chronicdiseases such as schizophrenia, which require prolonged exposure to thedrug.

[0048] Formula (I) compounds can be administered over a dosage rangegenerally varying from 0.02 to 200 mg/kg, depending upon the severity ofthe disease to be treated and its acute or chronic component. Dosesoutside the range indicated are, however, possible in particularconditions, under the supervision of a doctor.

[0049] The invention is now illustrated by means of the followingexamples.

EXPERIMENTAL PART 1. Chemistry

[0050] 1.1 Synthetic Approaches

[0051] The synthesis of the new pyrrolo[2,1-b][1,3]benzothiazepinestructure was accomplished by adopting the two retrosynthetic approachesdescribed in Schemes 1A and 2A. The synthesis is based on a cyclisationmethod to obtain the pyrrolobenzothiazepinone intermediate products9a,b. Scheme 1A gives our retrosynthetic analysis of compound 9a. Whenpyrrolo was treated with copper thiocyanate in methanol, thyocyanationoccurred in a few minutes, obtaining 2-thiocyanopyrrolo 11 with goodyields. The Grignard reaction with phenylmagnesium bromide (12),followed by alkylation with ethyl bromroacetate, produced ester 13 witha high overall yield.

[0052] Ester 13 may serve as a starting product in carrying out thecyclisation to 9a, on the basis of an acylation reaction promoted bycoppery(I). In fact, dimethyl aluminium methylselenolate was used toobtain selenoester 15. Like the thioesters, this selenoester could beused in the carbon-carbon bond formation reaction. Consequently, byexposure of 15 to the highly reactive crystalline complex of triatecopper(I) and benzene [(CuOTf)₂PhH], the tricylic compound 9a wasobtained together with ketone 16 and other unidentified reactionproducts.

[0053] Another synthesis method, shown in Scheme 2A, was based on athionium ion intermediate. This made it possible to prepare the keytricyclic intermediates 9a,b,c,d in conditions of Pummererrearrangement, starting from sulphoxide, which in turn were preparedfrom 1-[2-(methythio)phenyl]ethanones. As shown in Scheme 2B/1, the keyintermediate products 21a,b,c were prepared by brominiation of thecorresponding phenylethanones 18 and 20, which in turn were prepared,respectively, by reaction of methyllithium and the lithium salt of2-(methylthio)benzoic acid 17, or from (methylthio)benzene, 1-chloro- or1-fluoro-4-(methylthio)benzene 19a,b,c, with a Friedels-Crafts reactionwith acetic anhydride. Subsequently (SCHEME 2B/2), thebromophenylethanones 21a,b,c,d were transformed into the pyrrolederivatives 22a,b,c,d. Oxidation, for example with sodium periodate or3-chloroperbenzoic acid (MCPBA) (23a,b,c,d), followed by exposure ofthese sulphoxides to trifluoracetic anhycide produced the ketones9a,b,c,d with a yield of 40%. The mechanism proposed for the cyclisationstage is given in Scheme 2B/3.

[0054] The “interrupted” Pummerer rearrangement started with activationof the oxygen of the sulphoxide followed by attachment of the pyrrolering to the sulphur which shifted the trifluoracetic ion. The sulphoniumsalt then underwent the shift of the methyl group, generating the newheterocyclic system and methyltrifluoroacetate. Starting from theketones 9a,b,c,d (FIG. 2 B/2), the piperazine ring was introducedaccording to a standard method. Reduction of ketones 9a,b,c,d thenyielded the alcohols (±)-24a,b,c,d which were transformed into thecorresponding derivatives (±)-25a,b,c,d by means of PBr₃. By treating(±)-25a,b,c,d with N-methylpiperazine, the end product (±)-3a,b,c,d wasobtained. The thiazepine (±)-3a,b was resolved into the enantiomorphs(+)-3b and (−)-3b by means of HPLC, using a Chiralpak AD amylose column,or equivanent means.

[0055] 1.2 Materials and Methods

[0056] The melting points were determined using an Electrothermal 8103device and were not corrected. The IR spectra were recorded withPerkin-Elmer 398 and FT 1600 spectrophotometers. The ¹H-NMR spectra wererecorded with a Bruker 200 MHz spectrometer and a Varian 500 MHzspectrometer with TMS as internal standard; the chemical shift values(δ) are given in ppm and the coupling constants (J) in Hertz. Allreactions were carried out in an argon atmosphere. Progress of thereactions was monitored by TLC on silica gel plates (Riedel-de-Haen,Art. 37341). Merck silica gel (Kieselgel 60) was used for thechromatography columns (70-230 mesh) and for the flash chromatographycolumns (230-400 mesh). Exacts were dried on MgSO₄ and the solventsremoved at reduced pressure. The HPLC separation was carried out using aChiralpak AD Amylose column (097-702-40808) (length×diameter=250 mm×10mm). The elemental analyses were carried out on a Perkin-Elmer 240Celemental analyzer, and the results are within 0.4% of the theoreticalvalue, unless otherwise specified. The yields refer to purified,non-optimised products.

[0057] 1.3 Preparation of the Compounds

[0058] 2-(phenylthio)pyrrole (12)

[0059] To a solution of phenyl magnesium bromide (prepared frombromobenzene (0.75 ml) and magnesium chips (0.19 g, 7.8 mmol) inanhydrous THF (20 ml), cooled to 0° C., was slowly added a solution of2-thiocyanopyrrole 11 (0.5 g, 4.0 mmol) in anhydrous THF (20 ml). Afterstirring at 0° C. for 30 min, the mixture was poured into crushed iceand extracted with ethyl acetate. The organic phase was washed with 20%NH₄Cl, anhydride and evaporated. The residue was purified bychromatography (35% hexane in chloroform) to give 0.6 g (93% yield) of12 as colourless prisms: melting point 86-87° C. (hexane); IR (CHCl₃)3420 cm⁻¹; ¹H NMR (CDCl₃) δ8.20 (br s, 1H), 7.25-6.85 (m, 5H), 6.92 (m,1H), 6.55 (m, 1H), 6.31 (m, 1H). Anal. (C₉H₉NS): C, H, N.

[0060] Ethyl ester of 2-(phenylthio)pyrrole-1-acetic acid (13)

[0061] To a mixture of 18-Crown-6 (20 mg, 0.074 mmol) and potassiumterbutoxide (0.166 mg, 1.48 mmol) in anhydrous THF (5 ml) was added asolution of 12 (0.2 g, 1.14 mmol) in ahydrous THF (5 ml) under nitrogen.After 2 hours at ambient temperature, a solution of ethyl bromoacetate(0.254 ml, 2.28 mmol) in anhydrous THY (1 ml) was added dropwise. Afterstirring for 30 min at ambient temperature and the addition of 5 ml ofwater, the solvent was removed at reduced pressure and the residueextracted with EtOAc. The organic layers were washed with a saturatedsolution of NaCl, anhydrified and evaporated. The residue waschromatographed (30% hexane in chloroform) to give 0.28 g (96% yield) of13 as colourless prisms: melting point 101-102° C. (cyclohexane); IR(CHCl₃) 1760 cm⁻¹; ¹H NMR (CDCl₃) δ7.25-6.90 (m, 5H); 6.61 (m, 1H), 6.31(m, 1H), 4.68 (s, 2H), 4.05 (q, 2H, J=7.0 Hz), 1.14 (t, 3H, J=7.1 Hz).Anal. (C₁₄H₁₅NO₂S): C, H, N.

[0062] Methyl ester of 2-(phenylthio)pyrrole-1-selenoacetic acid (15)

[0063] A solution of dimethylaluminium methylselenolate (2.2 mmol)prepared by heating a solution of trimethylaluminium in toluene withselenium in powder form for 2 hours at reflux temperature under argon)in anhydrous toluene (1.1 ml) was added dropwise to a solution of 13(0.57 g, 2.2 mmol) in anhydrous dichloromethane (5 ml) cooled to 0° C.,under nitrogen. The mixture was agitated at 0° C. for 45 min, heated toambient temperature and stirred for another 45 min. Water (2 ml) wasadded and the mixture was extracted with EtOAc. The organic layers werewashed with a saturated NaCl solution, anhydrified and evaporated. Thecrude product was purified by distillation (85° C./0.1 mm Hg) to give0.6 g (97% yield) of 15 as a colourless oil: IR (t.q.) 1720 cm⁻¹; ¹H NMR(CDCl₃) δ7.24-6.95 (m, 6H); 6.69 (m, 1H), 6.37 (m, 1H), 4.69 (s, 2H),2.11 (s, 3H) m/z 311 (40, M⁺), 188, 155, 109, 91 (100). Anal.(C₁₃H₁₃SeNOS): C, H, N.

[0064] 1-[2-(methylthio)phenyl]ethanone (18)

[0065] To a suspension of lithium hydride (0.57 g, 6.7 mmol) inanhydrous 1,2-dimethoxyethane (5 ml), stirred vigorously, was addeddropwise a solution of acid 17 (1.0 g, 5.9 mmol) in anhydrous1,2-dimethoxyethane. The suspension was refluxed for 2,5 hours, cooledto −10° C. and added with methyl-lithium (4.2 ml, 6.7 mmol, 1,6 M) inthe space of 30 min. The reaction mixture was stirred for 2 hours atambient temperature. HCl 1N was added to the mixture, which wasextracted with ethyl ether. The organic layers were washed with asaturated NaCl solution, anhydrified and concentrated. Chromatography ofthe crude product (5% benzene in dichloromethane) gave 0.78 g (79%yield) of 18 as colourless prisms, the spectroscopic data for which wereidentical to those reported in the literature

[0066] 1-[5-chloro-2-(methylthio)phenyl]ethanone (20b)

[0067] A mixture of 19b (1.0 g, 6.3 mmol), anhydrous aluminium chloride(1.88 g, 13.5 mmol) and carbon sulphide (20 ml) was heated to refluxunder argon and acetic anhydride (0.46 ml, 6.3 mmol) was added dropwise.After reflux for 4 h, the solution was poured onto crushed ice and 20 mlof HCl 6N were added. The mixture was extracted with EtOAc and theorganic layers were washed with a saturated NaCl solution, anhydrifiedand concentrated. The oily residue was chromatographed (30% hexane inchloroform) to give 0.5 g (40% yield) of 20b as a waxy solid: IR (t.q.)1670 cm⁻¹; ¹H NMR (CDCl₃)δ7.83 (d, 1H, J=2.1 Hz); 7.44 (dd, 1H), 7.29(d, 1H, J=8.1 Hz), 2.63 (s, 3H), 2.41 (s, 3H). Anal. (C₉H₉CIOS): C, H

[0068] 2-Bromo-1-[2-(methylthio)phenyl]ethanone (21a).

[0069] The title compound was obtained starting from 18 and followingthe procedure as described below to obtain 21c. 21a was obtained ascolorless prism (69% yield):mp 81-82° C.(hexanes); IR (nujol) 1690 cm⁻¹,¹H NMR (CDCl₃)δ8.00-7.80 (m,2H), 7.35 (m,2H), 5.53 (s,2H), 2.27 (s,3H)Anal. (C₉H₉BrOS)C,H,

[0070] 2-Bromo-1-[5-chloro2(methylthio)phenyl]ethanone (21b).

[0071] The title compound was obtained starting from 20b and followingthe procedure as described below to obtain 21c. 21b was obtained ascolorless prism (620% yield); mp 97-98° C.(hexanes); IR (CHCl₃) 1685cm⁻¹; ¹H NMR (CDCCl₃) δ7.98-7.73 (m,3H), 5.57 (s,2H), 2.31 (s,3H).Anal.(C₉H₈BrClOS) C,H.

[0072] 1-[2-(methylthio)phenyl]-2-pyrrol-1-yl)ethanone (22a)

[0073] To a solution of 21a (2.1 g, 8.6 mmol) in 20 ml of anhydrous DMF,was added hexamethylene tetramine in portions. The solid formed wasfiltered, washed with chloroform and dried.

[0074] The hexamethylenetetrammonium sat thus obtained was added to aconcentrated HCl solution (3 ml) in 8 ml of ethanol.

[0075] The mixture was stirred for 96 hours in the dark at ambienttemperature. The white solid (NH₄Cl) was filtered d the solutionvacuum-concentrated.

[0076] The residue was crystallised by ethanol, and2-amino-1-[2-(methyl-thio)phenyl]ethanone hydrochloride was obtainedwith a yield of 78%; ¹H NMR (DMSO-d₆) δ8.43 (br s, 2H); 8.11-7.31 (m,5H), 4.59 (d, 2H, J=3.2 Hz), 2.46 (s, 3). Anal. (C₉H₁₂CINOS): C, H, N.

[0077] The 2-amino-1-[2-(methylthio)phenyl]ethaone hydrochloride wasdissolved in an aqueous solution of sodium acetate, glacial acetic acidand 2.5 dimethoxy tetrahydrofran. After stirring for 15 min at 100° C.,the mixture was cooled and extracted with ethyl acetate. The organiclayer was washed with NaHCO₃, dried and evaporated. The crude productwas chromatographed (CHCl₃) to give 22a with a yield of 50%: meltingpoint 113-114° C. (hexane); IR (nujol) 1690 cm⁻¹; ¹H NMR (CDCl₃)δ7.74-7.23 (m, 4H), 6.66 (m, 2H), 6.21 (m, 2H), 5.25 (d, 2H, J=3.4 Hz),2.44 (s, 3H). Anal. (C₁₃H₁₃NOS): C, H, N.

[0078] 1-[5-chloro-2-(methylthio)phenyl]-2-pyrrol-1-yl)ethanone (22b)

[0079] Starting from 21b (5.58 g, 20.0 mmol),2-amino-1-[5-chloro-2-(methyl-thio)phenyl]ethanone hydrochloride wasobtained using the procedure described in the previous example: yield75%; ¹H NMR PMSO-d₆) δ8.41 (br s, 2H); 8.10-7.28 (m, 3H), 4.48 (d, 2H,J=3.2 Hz), 2.42 (s, 3H). Anal. (C₉H₁₁CI₂NOS): C, H, N.

[0080] Starting from 2-amino-1-[5-chloro-2-(methylthio)phenyl]ethanonehydro-chloride, the titre compound was obtained as colourless prismsusing the procedure described to obtain 22a: 51% yield; melting point124-125° C. (hexane); IR (nujol) 1720 cm⁻¹; ¹H NMR (CDCl₃) δ7.62 (d, 1H,J=2.3 Hz); 7.45 (dd, 1H, J=8.2, 2.3 Hz), 7.29 (d, 1H, J=8.2 Hz), 6.65(m, 2H), 6.22 (m, 2H), 5.21 (s, 2H), 2.43 (s, 3H); ¹³C NMR (CDCl₃)δ194.2, 140.6, 134.5, 132.4, 130.1, 128.9, 127.7, 121.8, 109.2, 56.6,16.6. Anal. (C₁₃H12CINOS): C, H. N.

[0081] 1-[2-(methylsulphinyl)phenyl]-2-pyrrol-1-yl)ethanone (23a)

[0082] To a suspension of sodium periodate (0.55 g, 2.6 mmol) inmethanol (7 ml) and water (1.4 ml) was added a solution of 22a (0.6 g2.6 mmol) in methanol (2 ml). After stirring for 24 hours at ambienttemperature the sodium iodate was removed by filtration and the filtratewas evaporated. The residue was chromatographed (5% EtOAc indichloromethane) to give 0.59 g of 23a (92% yield) as colourless prisms:melting point 174-175° C. (ethanol); IR (nujol) 1710, 1090 cm⁻¹; ¹H NMR(CDCl₃) δ8.42-7.64 (m, 4H), 6.66 (m, 2H), 6.27 (m, 2H), 5.44 (0.5 ABq,1H, J=18.0 Hz), 5.27 (0.5 ABq, 1H, J=18.0 Hz), 2.80 (s, 3H). Anal.(C₁₃H₁₃NO₂S): C, H, N.

[0083] 1-[5-chloro-2-(methylsulphinyl)phenyl]-2-pyrrol-1-yl) ethanone(23b)

[0084] The titre compound was prepared starting from 22b (1.1 g, 4.45mmol) using the procedure described above for 23a; colourless prisms(89% yield): melting point 218-219° C. (ethanol); IR (nujol) 1710, 1080cm⁻¹; ¹H NMR (CDCl₃) δ8.37 (d, 1H, J=8.0 Hz); 7.85 (m, 2H), 6.66 (m,2H), 6.28 (m, 2H), 5.40 (0.5 Abq, 1H, J=17.7 Hz), 5.25 (0.5 Aq, 1H,J=17.8 Hz), 2.79 (s, 3H); ¹³C NMR (CDCl₃) δ193.4, 149.6, 136.9, 134.7,132.5, 128.8, 127.0, 121.8, 109.8, 55.7, 44.3. Anal. (C₁₃H₁₂CINO₂S): C,H, N.

[0085] 9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine-9-one (9a)

[0086] Method A: to a highly reactive solution of the crystallinecomplex of triflate copper(I) and benzene (0.81 g, 1.6 mmol) inanhydrous benzene (20 ml), cooled to 0° C., was added a solution ofselenoester 15 (0.5 g. 1,6 mmol) in anhydrous benzene (11 ml) and themixture was left to stir at ambient temperature for 16 hours. Ethylether (10 ml) was added, the organic phase was washed with ammonia 6N,anhydrified and concentrated. The crude product was chromatographed (5%hexane im dichloromethane) to give 51 mg of 9a (12% yield) as colourlessprisms. Ketone 16 (55% yield) was also recovered as a dense oil.Compound 9a: melting point 94-95° C. (hexane); IR (CDCl₃) 1690 cm⁻¹; ¹HNMR (CDCl₃) 3 8.14-7.30 (m, 4H); 6.88 (m, 1H), 6.42 (m, 1H), 6.12 (mn,1H), 5.15 (s, 2H); 13C NM (CDCl₃) δ190.9, 136.1, 133.3, 132.3, 130.8,127.6, 123.9, 120.2, 114.4, 109.2, 57.6. MS m/z 265 (10, M⁺), 215 (100),187, 154,115, 97. Anal. (C₁₂H₉NOS): C, H, N.

[0087] Compound 16: IR (t.q.) 1670 cm⁻¹; ¹H NMR (CCDl₃) δ7.22-6.81 (m,6H); 6.70 (m, 1H), 6.42 (m, 1H), 4.61 (s, 2H), 2.20 (s, 3H). MS m/z 231(100, M⁺). Anal. (C₁₃H₁₃NOS): C, H, N.

[0088] Method B: trifluoroacetic anhydride (1.0 ml, 7.4 mmol) was addeddropwise to just distilled N,N-dimethylformamide (8 ml) cooled to 0° C.After stirring for 20 min at 0° C., a solution of 23a (1.0 g, 4.0 mmol)was added in Just distilled N,N-dimethyl formamide (24 ml) and after 15min at 0° C. and 1 hour at ambient temperature, the pH of the dark redsolution was brought to 7 with NaOH 1N and the mixture was stirred foranother 30 min. Extraction with dichloromethane, anhydrification of theextracts and evaporation of the solvent gave an oily residue which waschromatographed (30% hexane in chloroform). Compound 9a was obtainedwith a 45% yield.

[0089] 7-chloro-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine-9-one(9b)

[0090] The titre compound was obtained with a yield of 42%, ascolourless prisms, starting from 23b and adopting the procedure asdescribed for 9a (Method B): melting point 106-107° C. (hexane); IR(CDCl₃) 1690 cm⁻¹; ¹H NMR (CDCl₃) δ8.14 (d, 1H, J=2.2 Hz); 7.49 (d, 1H,J=8.1 Hz), 7.38 (dd, 1H, J=8.0, 2.3 Hz), 6.88 (in, 1H), 6.43 (m, 1H),6.12 (m, 1H), 5.14 (s, 2H); ¹³C NMR (CDCl₃) δ189.7, 138.3, 133.3, 137.3,134.1, 133.1, 132.2, 131.9, 124.1, 119.5, 114.7, 109.5, 57.3. MS m/z 250(20, M⁺), 249 (100), 221, 216, 188, 158, 110. Anal. (C₁₂H₈CINOS): C, H,N.

[0091] (±)-9,10-dihydro-9-hydroxpyrrolo[2,1-b][1,3]benzothiazepine (24a)

[0092] To a solution of 9a (61 mg, 0.23 mol) in arhydrous methane (1ml), cooled to 0° C. and under nitrogen, were added aliquots of sodiumborohydride (80 mg, 0.23 mmol). After stirring for 1 hour at 0° C., thereaction was stopped with water (1 ml) and the mixture extracted withEtOAc. The organic layers were washed with brine, anhydrified andconcentrated. The residue was chromatographed (15% EtOAc indichloromethane) to give 24a (64 mg, 92% yield) as colourless prisms:melting point 101-102° C. (ethanol); IR (nujol) 3300 cm⁻¹; ¹H NMR(CDCl₃) δ7.47-7.12 (m, 4H), 6.86 (m, 1H), 6.33 (m, 1H), 6.02 (m, 1H),5.08 (m, 1H), 4.89 (dd, 1H, J=13.9, 1.7 Hz), 4.28 (dd, 1H, J=13.9, 6.0Hz), 2.05 (d, 1H, J=9.6 Hz). Anal. (C₁₂H₁₁NOS): C, H, N.

[0093](±)-7-chloro-9,10-dihydro-9-hydroxpyrrolo[2,1-b][1,3]benzothiazepine(24b)

[0094] The titre compound was obtained starting from 9b (112 mg, 0.45mmol) using the procedure described above: 88% yield; melting point118-119° C. (ethanol); IR (CHCl₃) 3300 cm⁻¹; ¹H NMR (CDCl₃) δ7.48 (d,1H, J=2.1 Hz); 7.32 (d, 1H, J=8.0 Hz), 7.15 (dd, 1H, J=8.1, 2.1 Hz),6.88 (m, 1H), 6.34 (m, 1H), 6.11 (m, 1H), 5.02 (m, 1H), 4.85 (dd, 1H,J=13.9, 1.9 Hz), 4.29 (dd, 1H, J=13.9, 6.6 Hz), 2.10 (dd, 1H, J=9.6 Hz).Anal (C₁₂H₁₀CINOS): C, H, N.

[0095] (±)-9-bromo-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine (255a)

[0096] To a solution of 24a (0.26 g, 1.0 mmol) in anhydrous ethyl ether(4 ml) was added dropwise a solution of PBr3 (0.13 g, 0.5 mmol) inanhydrous ethyl ether (1 ml) and the reaction mixture was kept at refluxtemperature for 2 hours under nitrogen. Anhydrous ethanol was added (0.2ml) and the resulting solution was heated to reflux temperature foranother hour. Five ml of an aqueous solution of 5% Na₂CO₃ were thenadded, the organic phase was separated, anhydrified and evaporated. Thecrude product was chromatographed (hexane and chloroform 1:1) to give25a (0.2 g, 64% yield) as colourless prisms: melting point 115-116° C.(cyclohexene); ¹H NMR (CDCl₃) δ7.46-7.09 (m, 4H); 6.93 (m, 1H), 6.39 (m,1H), 6.12 (m, 1H), 5.75 (dd, 1H, J=6.9, 2.6 Hz), 5.07 (dd, 1H, J=14.7,2.6 Hz), 4.61 (dd, 1H, J=14.7, 6.9 Hz). Anal. (C₁₂H₁₀BrNOS): C, H, N.

[0097](±)-9-bromo-7-chloro9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine (25b)

[0098] The titre compound was obtained starting from 24b (0.31 g, 1.6mmol) using the procedure described above: 51% yield; melting point106-107° C. (cyclohexane); ¹H NMR (CDCl₃) 5 7.45 (d, 1H, J=2.1 Hz); 7.27(d, 1H, J=8.6 Hz), 7.11 (dd, 1H, J=8.6, 2.1 Hz), 6.92 (m, 1H), 6.39 (m,1H), 6.12 (m, 1H), 5.63 (dd, 1H, J=7.0, 2.3 Hz), 5.06 (dd, 1H, J=14.4,2.3 Hz), 4.61 (dd, 1H, J=14.0, 7.0 Hz). ¹³C NMR (CDCl₃) δ139.9, 134.1,133.2, 131.7, 131.5, 128.9, 125.6, 119.6, 114.6, 108.1, 51.2, 51.0.Anal. (C₁₂H₉BrCINOS): C, H, N.

EXAMPLE 1

[0099](±)-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]enzo-thiazepine(3a)

[0100] A mixture of 25a (0.65 g, 2.0 mmol) and N-methylpiperazine (1.1ml, 10.0 mmol) was heated to 130° C. for 2 hours under argon, cooled,poured onto crushed ice and extracted with ethyl ether. The organicextracts collected were washed with brine, anhydrified. andconcentrated. The residue was chromatographed (EtOAc) to give 0.45 g(75% yield) of 3a as colourless prisms: melting point 206-207° C.(hexane); ¹H NMR (CDCl₃) δ7.49-7.09 (m, 4H); 6.87 (m, 1H), 6.29 (m, 1H),4.68 (dd, 1H, J=14.4, 8.6 Hz), 4.51 (dd 1H, J=14.4, 3.7 Hz), 2.56-2.34(m, 8H), 2.23 (s, 3H); ¹³C NMR (CDCl₃) δ138.1, 134.6, 132.9, 130.4,127.3, 126.9, 123.9, 121.7, 113.3, 107.7, 66.1, 55.9, 48.8, 46.6. 46.1.MS m/z 299 (100, M⁺), 219, 200, 167, 149, 113. Anal. (C₁₇H₂₁N₃S) C, H,N.

EXAMPLE 2

[0101](±)-7-chloro9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine(3b) (ST1455)

[0102] The titre compound was obtained starting from 25b (0.3 g, 0.95mmol) using the procedure described above. 3b was obtained as colourlessprisms (68% yield): melting point 210-211° C. (hexane); ¹H NMR (CDCl₃)δ7.51 (d, 1H, J=2.4 Hz); 7.30 (d, 1H, J=8.5 Hz), 7.06 (dd, 1H, J=8.5,2.4 Hz), 6.86 (m, 1H), 6.29 (m, 1H), 6.05 (m, 1H), 4.71 (dd, 1H, J=14.0,8.6 Hz), 4.45 (dd, 1H, J=14.0, 3.4 Hz), 3.95 (dd, 1H, J=8.6, 3.4 Hz),2.65-2.25 (m, 8H), 1.42 (s, 3H); ¹³C NMR (CDCl₃) δ140.1, 133.2, 133.0,132.4, 131.6, 127.3, 123.9, 121.1, 113.6, 107.9, 65.9, 55.8, 55.7, 47.7,45.9, 44.9, 26.8. MS m/z 333 (10, M⁺), 250, 233 (100), 201, 166, 139.Anal. (C₁₇H₂₀CIN₃S): C, H, N. The dihydrochloride salt (namedhereinafter ST1468) was obtained by dissolving an analytical sample inHCl 1N in methanol. The solvent was evaporated and the residuerecrystallized (methanol and ethyl ether 1:1). Anal. (C₁₇H₂₂CI₃N₃S), C,H, N.

EXAMPLE 3

[0103] Semipreparatory Chiral Separation of (±)-3b

[0104] First of all, the hydrochloride salt of (±)-3b was purified on ashort column filled with silica gel, using dichloromethane and methanol(9:1) as the eluent. The purified solvent was converted to the freebase. Evaporation of the solvent gave an oily residue which wasdissolved in isopropanol and the solution was diluted with hexane untilthe 95:5 ratio was obtained. For the separation of the enantiomers, a10-15 mg/ml concentration of the racemic mixture was made. A mixture ofhexane (plus 0.1% triethylamide) and isopropanol was used as the mobilephase.

[0105] A gradient-type mixer maintained the ratio between the solventshexane and isopropanol at 95:5. Injection amounts were 100 μl perinjection. The enantiomers were collected using a fraction collector.Only fractions with a signal above 10% (10 mV) of the total scale werecollected. The amounts with signals below 10% were collected separatelyand used for a second purification. The purity of both enantiomers wasdetermined by weighing the trace peaks separately.

[0106] (+)-3b: ¹H NMR (500 Mhz, CDCl₃) δ7.52 (d, 1H, J=2.4 Hz); 7.32 (d,1H, J=8.3 Hz), 7.09 (dd, 1H, J=2.4, 8.3 Hz), 6.88 (m, 1H), 6.30 (n, 1H),6.07 (m, 1H), 4.71 (dd, 1H, J=8.8, 14.2 Hz), 4.50 (dd, 1H, J=3.9, 14.7Hz), 3.97 (dd, 1H, J=3.4, 8.8 Hz), 2.55 (m, 4H), 2.40 (m, 4H), 2.27 (s,3H); ¹³C NMR (500 MHz, CDCl₃) δ139.9, 133.0, 132.9, 132.3, 131.6, 127.3,123.8, 121.0, 113.5, 107.9, 88.2, 65.8, 55.6, 48.6, 45.9, 45.8; purity(ee) 94.6%; [α]_(D)=+46.0° (c 0.48, MeOH). The respectivedihydrochloride, obtained as in the case of compound (±)3b, was namedST1469.

[0107] (−)-3b: ¹H NMR (500 Mhz, CDCl₃) δ7.53 (d, 1H, J=2.3 Hz); 7.32 (d,1H, J=8.3 Hz), 7.09 (dd, 1H, J=6.8 Hz), 6.88 (m, 1H), 6.30 (m, 1H), 6.07(m, 1H), 4.71 (dd, 1H, J=9.3, 14.5 Hz), 4.48 (dd, 1H, J=3.4, 14.2 Hz),3.98 (dd, 1H, J=2.9, 8.8 Hz), 2.49 (m, 8H), 2.27 (s, 3H); ¹³C NMR (500MHz, CDCl₃) δ140.0, 133.0, 132.9, 132.3, 131.6, 127.3, 123.8, 121.0,113.5, 107.9, 88.2, 65.8, 55.6, 48.6, 45.9, 45.8; purity (ee) 98%;[α]_(D)=−47.90 (c 0.54, MeOH). The respective dihydrochloride, obtainedas in the case of compound (±)3b, was named ST1470.

EXAMPLE 4

[0108] (±)-7-Fluoro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1b][1,3]benzothiazepine (3c) (ST1456)

[0109] The synthesis of the (3c) was been performed as described inScheme 2B/1 and 2B/2 where c=F.

[0110] 1-[5-Fluoro-2-(methylthio)phenyl]ethanone (20c).

[0111] A mixture of 4-fluorothioanisole (19c) (4 g, 28.13 mmol),anhydrous aluminium chloride (8.40 g, 63.02 mmol) and carbon disulphide(89 ml) was heated at reflux under argon atmosphere, and aceticanhydride (2.65 ml, 28.07 mmol) was added dropwise in 2 h. Afterreflexing for 24 h, the solution was poured into crushed ice, water(62.48 ml) and concentrated hydrochloric acid (2.68 ml). The organicphase was separated and water exacted with dichloromethane (3×30 ml),the organic layers were washed with brine, dried and concentrated. Theoily residue was chromatographed (50% petroleum ether 40-60° indichioromethane) to afford 20c (2.98 g) as a colourless crystallinesolid, mp 82.0-84.3° C. (58% yield). ¹NMR (CDCl₃) δ7.49-7.43 (dd, 1H,J=9.23, 2.44 Hz); 7.29-7.11 (m, 2H); 2.57 (s, 3H); 2.39 (s, 3H).

[0112] 2-Bromo-1-[5-fluoro-2-(methylthio)phenyl]ethanone (21 c).

[0113] To a sting solution of 20c (2.07 g, 11.34 mmol), carbontetrachloride (62 ml) and glacial acetic acid (2.07 ml) was added atroom temperature a solution of bromine (μL 546.6, 10.66 mmol) in carbontetrachloride (34 mmol). The first drop was added and after 20 minutesthe solution was added dropwise in 4 hours. After stirring for 16 hoursthe solvent was distilled and to the residue was added water and solidsodium bicarbonate (to pH 7), the organic phase was separated and waterextracted with dichioromethane (3×30 mn), the organic layers were driedand evaporated. The crude product was chromatographed (70% petroleumether 40-60° in dichloromethane) to give 1.90 g of 21c as a yellowishsolid (64% yield). ¹NMR (CDCl₃) δ7.47-7.42 (dd, 1H, J=8.85, 2.84 Hz);7.38-7.18 (m, 2H); 4.42 (s, 2H); 2.43 (s, 3H).

[0114] 1-[5-Fluoro-2-(methylthio)phenyl]-2-(pyrrol-1-yl)ethanone (22c).

[0115] To a stirring solution of hexamethylenetetramnine (3.18 g, 22.70nmol) in chloroform (29.6 ml) at room temperature was added dropwise in5 minutes a solution of 21c (1.90 g, 7.20 mmol) in chloroform (16 ml).As soon as the solid formed the solution was rapidly filtered and thedesired product was collected as a yellow amorphous solid that waswashed with chloroform, dried and used for the following reaction; (99%yield).

[0116] A suspension of1-[5-fluoro-2-(methylthio)phenyl]ethanon-2-hexaminium bromide (1.62 g,4.02 mmol) in methanol (13.3 ml) was warmed to 0° C. and was added ofconcentrated hydrochloric acid (1.86 ml). The mixture was stirred for 96hours in the dark at room temperature. The white solid (ammoniumchloride) was removed by filtration and the obtained solution wasevaporated. The residue was recrystallized from ethanol to give2-amino-1-[5-fluoro-2-(methylthio)phenyl]ethanone hydrochloride as ayellow solid, that was used in the next step without furtherpurification. (98% yield).

[0117] To a solution of2-amino-1-[5-fluoro-2-(methylthio)phenyl]ethanone hydrochloride (4.54 g,19.27 mmol) in water (29 ml), heated at 90° C., were added trihydratedsodium acetate (2.62 g, 19.27 mmol), glacial acetic acid (17 ml) and2,5-dimethoxytetrahydrofuran (2.40 ml, 18.50 mmol). After 20 seconds at90-100° C. the mixture was cooled and extracted with ethyl acetate. Theorganic layers were washed with a 20% solution of sodium bicarbonate andbrine, dried ad evaporated. The residue was chromatographed (50%petroleum ether 40-60° in dichloromethane) to afford 2.07 g of 22c aswhite crystals mp 133.2-134.0° C. (50% yield). ¹NMR (CDCl₃) δ7.39-7.15(m, 3H); 6.66-6.65 (m, 2H); 6.22-6.20 (m, 2H); 5.20 (s, 2H); 2.42 (s,3H). MS m/z 252 (M⁺+H), 234, 202 (100), 183, 169, 154, 141, 126, 109,80.

[0118] 1-[5-Fluoro-2-(methysulfinyl)phenyl]-2-(pyrrol-1-yl)ethanone(23c).

[0119] To a stirred cooled solution of1-[5-Fluoro-2-(methylthiophenyl]-2-(pyrrol-1-yl)ethanone (22c) (1.76 g,7.06 mmol) in dichloromethane (12 ml) was added dropwise in 30 minutes asolution of m-chloroperbezoic acid (71.5% grade, 1.70 g, 7.06 mmol) indichioromethane (10 ml). After stirring for 45 minutes at 0° C., themixture was treated with a 5% solution of sodium carbonate in water (41ml) and was stirred for 15 minutes at room temperature. The organicphase was separated and water was exacted with dichloromethane (3×10ml). The organic layers were dried and evaporated, the residue waschromatographed (10% dichloromethane in ethyl acetate) to afford 1.02 gof 23c as white crystals that darkened rapidly (64% yield). ¹NMR (CDCl₃) δ8.42-8.35 (m, 1H); 7.61-7.51 (m, 2H); 6.68-6.62 (m, 2H); 6.26-6.24(m, 2H); 5.41-5.17 (q, 2H, J=31.32, 17.87 Hz); 2.77 (s, 3H).

[0120] 7-Fluoro-9,10-dihydropyrrolo[2,1-b][1,3]benzotiazepin-9-one (9c).

[0121] Trifluoroacetic anhydride (1.02 ml) was added dropwise underargon atmosphere to a freshly distilled N,N-dimethylformamide (8 ml)cooled to 0° C. After s ting for 20 minutes at 0° C. a solution of 23c(109 g, 4.12 mmol) in N,N-dimethylformamide (29 ml) was added. After 15minutes at room temperature water (41 ml) was added to the dark yellowsolution and pH was adjusted to 7 with sodium acetate, the mixtureobtained was stirred at room temperature for 1 night. Extraction withdichloromethane, drying of the eracts, and evaporation of the solventgave an oily residue which was chromatographed (30% petroleum ether40-60° in dichloromethane). The compound 9c was crystallised fromn-hexane as yellowish crystals mp 133.8-134.2° C. (20% yield). ¹H NMR(CDCl₃) δ7.82-7.76 (m, 1H);7.55-7.49 (m, 1H); 7.18-7.09 (m, 1H);6.88-6.87 (m, 1H); 6.42-6.40 (m, 1H); 6.12-6.09 (m, 1H); 5.14 (s, 2H).MS m/z 233 (100) (M+), 205, 200, 172, 126.

[0122](±)-7Fluoro-9,10-dihydro-9-hydroxpyrrolo[2,1-b][1,3]benzothiazepine(24c).

[0123] To a solution of 9c (0.037 g 0.16 mmol) in dry tetrahydrofuran(0.5 ml) and dry methanol (0.7 ml), cooled to 0°0 C. under argonatmosphere, was added in portions sodium borohydride (0.09 g, 0.16mmol). After stirring for 1 hour at 0° C. the reaction was quenched witha saturated solution of ammonium chloride (1 ml), the solvent wasremoved and the mixture was extracted with ethyl acetate (3×2 ml). Theorganic layers were dried and evaporated, the crude product waschromatographed (30% petroleum ether 40-60° in dichloromethane) to give24c 0.036 g (96% yield). 1H NMR (CDCl₃) δ7.40-7.33 (m, 1H); 7.24-7.18(m, 1H); 6.93-6.84 (m, 2H); 6.33-6.31 (m, 1H); 6.11-6.08 (m, 1H);5.12-5.04 (m, 1H); 4.91-4.83 (dd, 1H, J=14.22, 2.25 Hz); 4.34-4.24 (dd,1H, J=14.02, 6.51 Hz); 2.09-2.04 (d, 1H, J=9.83 Hz).

[0124](±)-9-Bromo-7-fluoro-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine(25c).

[0125] To a solution of 24c (0.17 g 0.71 mmol) in dry ethyl ether (3 ml)was added dropwise a solution of phosphorus tribromide (μL 33.5, 0.36mmol) in dry ethyl ether (0.7 ml); the reaction mixture was refluxed for2 hours under argon atmosphere. After cooling to room temperature dryethanol (μL 143) was added and the resulting solution was heated atreflux for 1 hour. Then 4 ml of aqueous sodium carbonate was added; theorganic phase was separated, dried and evaporated. The crude product waschromatographed (50% petroleum ether 40-60° in dichloromethane) to give0.103 g of pure 25c (48% yield). ¹H NMR (CDCl₃) δ7.35-7.16 (m, 2H);6.92-6.82 (m, 2H); 6.39-6.37 (m, 1H); 6.13-6.09 (m, 1H); 5.69-5.64 (m,1H); 5.10-5.01 (dd, 1H, J=14.57, 2.65 Hz); 4.70-4.59 (dd, 1H, J=14.88,7.05 Hz)

EXAMPLE 5

[0126](±)-7-Fluoro-9-(4methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1b][1,3]benzothiazepine(3c)ST 1456.

[0127] A mixture of 25c (0.05 g, 0.18 mmol) and N-methylpiperazine (1ml) was heated at 140° C. for 17 hours under argon atmosphere. Thereaction mixture was then cooled, diluted with ethyl acetate (30 ml) andwashed with brine. The organic layers were dried, evaporated and theoily residue was chromatographed (10% trimethylamine in ethyl acetate)to afford 0.037 g of 3c as a colourless solid mp 213-214° C. (63%yield). ¹NMR (CDCl₃) δ7.37-7.26 (m, 2H); 6.85-6.76 (m, 2H); 6.29-6.27(m, 1H); 6.06-6.03 (m, 1H); 4.78-4.67 (m, 1H); 4.49-4.40 (dd, 1H,J=14.19, 3.48 Hz); 3.99-3.93 (dd, 1H, J=8.97, 3.39 Hz); 2.64-2.37 (m,8H); 2.25 (s, 3H). MS m/z 318 (100) (M⁺+H), 277, 218, 185.

EXAMPLE 6

[0128](±)-7-Fluoro-9-(4ethylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine(4c)ST1457.

[0129] The desired product 4c was obtained starting from 25c (0.053 g,0.178 mmol), using 4-methylpiperazine (1 ml). The colourless liquid 4cwas obtained with 73% yield. 1H NMR (CDCl₃) δ7.37-7.26 (m, 2H);δ6.86-6.75 (m, 2H); 6.29-6.26 (m, 1H); 6.05-6.02 (m, 1H); 4.80-4.68 (mn,1H); 4.48-4.39 (dd, 1H, J=13.95, 3.78 Hz); 3.97-3.91 (dd, 1H, J=9.23)3.65 Hz); 2.60-2.32 (m, 10H); 1.08-1.00 (t, 3H, J=7.33 Hz). MS m/z 332(100) (M⁺+H), 277, 218, 185, 115.

EXAMPLE 6

[0130](±)-7-Fluoro-9-[4-(2′-hydroxyethyl)piperazin-1-yl]-9,10-dihydropyrrolo[2,1b][1,3]benzothiazepiue(5c) ST 1458.

[0131] A solution of 25c (0.065 g, 0.218 mmol) hydroxyethylpiperine (μL59, 0.218 mmol) and 2-buthanone (2 ml) was refluxed for 21 hours. Thereaction ixte was then evaporated and to the residue was added water andwas extracted with ethyl acetate, combined extracts were dried andevaporated. The crude product was chromatographed to give 5c as acolourless amorphous solid (69% yield). ¹H NMR (CDCl₃) δ7.37-7.24 (m,2H); 6.86-6.77 (m, 2H); 6.29-6.27 (m, 1H); 6.06-6.03 (m, 1H); 4.77-4.65(m, 1H); 4.48-4.40 (dd, 1H, J=14.15, 3.46 Hz); 3.98-3.92 (dd, 1H,J=8.93, 3.50 Hz); 3.59-3.54 (t, 2H, J=5.37 Hz); 2.85 (bs, 1H); 2.57-2.47(m, 10H). MS m/z 348 (100) (M³⁰+H) 288, 218, 185.

EXAMPLE 7

[0132](±)-7-Bromo-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine(3d).

[0133] The synthesis of the (3d) was been performed as described inScheme C and 2B/2 where d=Br.

[0134] Bis-(2-hydroxycarbonyl-4-bromo)phenyldisulphide (26).

[0135] To a cooled (0-5° C.) sing solution of 2-amino-5-bromobenzoicacid (1 g, 4.63 mmol), sodium hydroxide (0.185 g, 4.63 mmol), water(7.71 ml) and sodium nitrite (0.32 g, 4.63 mmol) was slowly added asolution of concentrated hydrochloric acid (1.44 ml) in water (2.5 ml),the mixture was stirred at 0-5° C. for 1 h, than was neutralised withpotassium carbonate and potassium acetate. The cold diazonium saltsolution was run into a vigorously stirred solution of potassium ethylxanthate (2.23 g, 13.89 mmol) and water (7.7 ml) previously heated at75-80° C. and was maintaining this temperature during addition and forher 1 h. The reaction mixture was cooled to room temperature and stirredfor 1 h. Than hydrogen peroxide (3.22 ml) was added and the solution wasstirred for 1 night at room temperature. The xue was filtered and thesolution was acidified (on an ice bath) and filtered again. The productthat was collected as a yellow amorphous solid was dissolved withaqueous sodium hydroxide and reprecipitated with hydrochloric acid toafford pure 26 (1.02 g) (95% yield). The compound was used in the nextstep without further purification

[0136] 1-[5-Bromo-(2-methylthio)phenyl]hydroxycarbonyl (27).

[0137] To a solution of (26) (1 g, 2.15 mmol) in 85% ethanol (17.2 ml)and sodium hydroxide, sodium borohydride (0.163 g) was added inportions. The resulting solution was stirred 30 minutes at roomtemperature and for additional 3 hours at reflux. Then ice was added andthe mixture was stirred for 15 minutes at room temperature, a solutionof sodium hydroxide (0.302 g, 7.55 mmol) in water (1.9 ml) and dimethylsulphide (376 μL, 3.97 mmol) were added and the reaction mixture wasstirred 2.5 hours at reflux. After cooling 1 drop of ammonium hydroxide30% was added (to destroy the excess of sodium hydroxide), hydrochloricacid was added (pH 3). The solid obtained was collected by filtration.The crude product was chromatographed (4% formic acid, 20% ethyl acetatein toluene) to afford 1.017 g of 27 as a yellow solid (96% yield). 1HNMR (DMSO-d₆) δ7.95-7.94 (d, 1H, J=2.69 Hz); 7.72-7.66 (dd, 1H, J=8.80,1.95 Hz); 7.29-7.25 (d, 1H, J=8.77 Hz); 2.37 (s, 3H).

[0138] 1-[5-Bromo-(2-methylthio)phenyl]ethanone (28).

[0139] A stirred solution of (27) (0.1 g, 0.40 mmol) in drytetrahydrofran (3.03 ml) was cooled to 0° C. (ice bath) and treated withmethyllithium (1.4 M solution in ether, 1.156 ml. 1.62 mmol). After 2hours at 0° C. under sing, tirethylchorosilane (1.03 ml, 8.09 mmol) wasrapidly added while stirring continued, the ice bath was removed and thereaction mixture was allowed to came to room temperature, then 1 Nhydrochloric acid (3.05 ml) was added and the resulting two phase systemwas stirred at room temperature for 30 minutes. The organic phase wasseparated and water was extracted with ether (3×5 ml), the combinedextracts were dried and evaporated. The crude product waschromatographed (30% petroleum ether 40-60° in dichloromethane) toafford 0.064 g of 28 as a yellowish solid mp 71.5-73.0° C. (64% yield).¹H NMR (CDCl₃) δ7.89-7.88 (d, 1H, J=1.91 Hz); 7.57-7.51 (dd, 1H, J=8.45,2.48 Hz); 7.18-7.14 (d, 1H, J=8.48 Hz); 2.58 (s, 3H); 2.39 (s, 3H).

[0140] 2-Bromo-1-[5-bromo-2-(metylthio)phenyl]ethanone (21 d).

[0141] Starting from 28 (0.60 g, 2.43 mmol), the desired product 21d wasobtained following the procedure described for 21c. The crude productwas chromatographed (50% petroleum ether 40-60° in dichloromethane) togive the pure product 0.57 g. (72% yield). ¹H NMR (CDCl₃) δ7.87-7.58 (d,1H, J=1.60 Hz);7.48-7.42 (dd, 1H, J=8.05, 2.08); 7.12-7.16(d, 1H, J=8.06Hz); 4.43 (s, 2H); 2.43 (s, 3H)

[0142] 1-[5-Bromo-2-(methylthio)phenyl]-2-(pyrrol-1-yl) ethaone (22d).

[0143] The desired product 22d was obtained as white crystals, followingthe procedure described for 22c; mp 138.0-139.2° C. (32% yield). ¹H NMR(CDCB) δ7.76-7.55 (d, 1H, J=1.92 Hz);7.60-754 (dd, 1H, J=8.43, 2.16Hz);7.23-7.19 (d, 1H, J=8.82 Hz); 6.65-6.63 (m, 2H); 6.22-6.20 (m, 2H);5.20 (s, 2H); 2.41 (s, 3H).

[0144] 1-[5-Bromo-2-(methylsulfylphenyl]-2-(pyrrol-1-yl)ethanone (23d).

[0145] Starting from 22d (0.27 g, 0.86 mmol), the desired product wasobtained following the above-described procedure, as white crystals mp138.0-139.2° C. (75% yield) ¹H NMR (CDCl₃) δ8.30-8.25 (m, 1H); 8.0-7.96(m, 2H); 6.64-6.62 (m, 2H); 6.27-6.25 (ml, 2H); 5.43-5.18 (q, 2H,J=32.28, 17.92 Hz); 2.77 (s, 3H).

[0146] 7-Bromo-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine-9-one (9d)

[0147] The reaction to obtain 9d was carried out, accordingly theprocedure described for 9c, using trifluoroacetic acid as solvent (0.63ml) and adding solid 23d (0.20 g, .062 mmol) to the cold (0° C.)solution of trifluoroacetic acid and trifluoroacetic anhydride. Thedesired product 9d was obtained as yellowish crystals (64% yield). ¹HNMR (CDCl₃) δ8.22-8.21 (d, 1H, J=1.99 Hz);7.56-7.51 (dd, 1H, J=8.28,2.24 Hz); 7.42-7.38 (d, 1H, J=8.42 Hz); 6.87-6.86 (m, 1H); 6.43-6.41 (m,1H); 6.12-6.09 (m, 1H); 5.13 (s, 2H). MS m/z 293 (100) (M⁺), 265, 261,232, 214, 186, 154, 115.

[0148](±)-7-Bromo-9,10-dihydro-9-hydroxpyrrolo[2,1-b][1,3]benzothiazepine(24d).

[0149] Starting from 9d (0.12 g, 0.39 mmol), the desired product wasobtained accordingly the procedure described for 24c (65% yield). ¹NMR(CDCl₃) δ7.63-7.62 (d, 1H, J=1.70 Hz); 7.32-7.21 (m, 2H); 6.88-6.87 (m,2H); 6.34-6.32 (m, 1H); 6.12-6.09 (m, 1H); 5.02 (s, 1H; 4.90-4.82 (dd,1H, J=13.86, 1.83 Hz); 4.36-4.25 (dd, 1H, J=14.18, 6.33 Hz); 1.99(s, 1H)

[0150] (±)-7,9-dibromo-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine(25d).

[0151] Starting from 24d (0.07 g, 0.25 mmol) the title compound wasobtained following the above-described procedure (36% yield). 1H NMR(CDCl₃) δ7.59 (i, 1H); 7.28-7.16 (m, 2H); 6.92-6.91 (m, 1H); 6.39-6.37(m, 1H); 6.13-6.10 (m, 1H); 5.65-5.60 (dd, 1H, J=6.98, 2.57 Hz);5.09-5.00 (dd, 1H, J=14.65, 2.35 Hz); 4.66-4.55 (dd, 1H, J=14.68, 7.03Hz).

[0152](±)-7-Bromo-9-(4methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine(3d).

[0153] Starting from 25d (0.033 g, 0.092 mmol) the title compound wasobtained following the procedure described for 3c (58% yield). ¹H NMR(CDCl₃) δ7.64 (s, 1H); 7.35-7.21 (m, 2H); 6.86-6.84 (m, 1H); 6.29-6.26(m, 1H); 6.06-6.02 (m, 1H); 4.73-4.61 (m, 1H); 4.49-4.40 (dd, 1H,J=14.30, 8.57 Hz); 3.98-3.92 (dd, 1H, J=8.64, 3.53 H/z); 2.57-2.37 (m,11H).

[0154] 2. Pharmacology

EXPERMENTAL PROCEDURES In Vitro Binding Assay

[0155] D₁,D₂,D₃ and 5-HT_(2a) affinity.

[0156] Male CRL:CD(SD)BR-COBS rats (Charles River, Italy) were killed bydecapitation (procedures involving animals and their care were conductedin conformity with the institutional guidelines that are in compliancewith national (D.L. n. 116, G.U., suppl. 40, Feb. 18, 1992) andinternational laws and policies (EEC Council Directive 86/609, OJ L 358,1, Dec. 12, 1987; Guide for the Care and Use of Laboratory Animals,U.S.National Research Council, 1996); their brains were rapidly dissectedinto the various areas (striatum for DA-₁ and DA-₂ receptors, olfactorytubercle for DA-₃ receptors and cortex for 5-HT_(2A) receptors) andstored at −80° C. until the day of assay. Tissues were homogemnsed inabout 50 volumes of Tris HCl, 50 mM, pH 7.4 (for DA-₁, DA-₂ and5-HT_(2A) receptors) or Hepes Na, 50 mM, pH 7.5 (for DA-₃ receptors),using an Ultra Turrax TP-1810 (2×20 sec.), and centriuged at 50000 g for10 min. The pellets were resuspended in fresh buffer, incubated at 37°C. for 10 min and centrifuged as before. The pellets were then washedonce by resuspension in fresh buffer and centrifuged again. The pelletsobtained were resuspended in the appropriate incubation buffer (TrisHCl, 50 mM, pH 7.1, containing 10 μM pargyline, 0.1% ascorbic acid, 120mM NaCl, 5 mM KCl, 2 mM CaCl₂, 1 mM MgCI₂ for DA-₁ and DA-₂ receptors;Hepes Na, 50 mM, pH 7.5, containing 1 mM EDTA, 0.005% ascorbic acid,0.1% albumin, 200 nM eliprodil for DA-₃ receptors) just before thebinding assay.

[0157] [³H]SCH 23390 (specific activity 70.3 Ci/mmol, NEN) binding toDA-₁ receptors was assayed in a final incubation volume of 0.5 ml,consisting of 0.25 ml of membrane suspension (2 mg tissue/sample)) 0.25ml of [³H]ligand (0.4 nM) and 10 μl of displacing agent or solvent.Non-specific binding was obtained in the presence of 10 μM(−)-cis-flupentixol.

[0158] [³H]Spiperone (specific activity 16.5 Ci/mmol, NEN) binding toDA-₂ receptors was assayed in a final incubation volumne of 1 ml,consisting of 0.5 ral of membrane suspension (1 mg tissue/samnple), 0.5ml of [³H]ligand (0.2 nM) and 20 μl of displacing agent or solvent.Non-specific binding was obtained in the presence of 100 M (−)sulpiride.

[0159] [³H]-7-OH-DPAT (specific activity 159 Ci/mmol, Amersham) bindingto DA-₃ receptors was assayed in a final incubation volume of 1 ml,consisting of 0.5 ml of membranes suspension (10 mg tissue/sample), 0.5ml of [³H]ligand and 20 μl of displacing agent or solvent. Non-specificbinding was obtained in te presence of 1 μM dopamine.

[0160] [³H]Ketanserin (specific actvity 63.3 Ci/mol, NEN) binding to5-HT_(2A) receptors was assayed in a final incubation volume of 1 mlconsisting of 0.5 ml of minebrane suspension (5 mg,tissue/sample), 0.5ml of [³H]ligand (0.7 nM) and 20 μl of displacing agent or solvent.Non-specific binding was obtained in the presence of 1 μM methysergide.Incubations (15 min at 37° C. for DA-₂ and 5-HT_(2A) receptors; 15 minat 25° C. for DA-₁ receptors; 60 min at 25° C. for DA-₃ receptors) werestopped by rapid filtration under vacuum through GF/B (for DA-₁, DA-₂and 5-HT_(2A) receptors) or GF/C (for DA-₃ receptors) filters which werethen washed with 12 ml of ice-cold buffer) using a Brandel M-48R. Theradioactivity trapped on the filters was counted in 4 ml of Ultima GoldMV (Packard) in a LKB 1214 rack beta liquid scintillation spectrometerwith a counting efficiency of 60%.

[0161] H₁ affinity

[0162] Whole cortexes from imale Fischer rats (300-350 g) werehomogenised with a Polytron in nine volumes (w/v) of 50 mzM Na⁺-K⁺phosphate buffer (pH 7.5). The homogenate was centrifuged at 16500× gfor 10 min and the particulate fraction was resuspended in the originalvolume of buffer. In a typical experiment, aliquots of the homaogenate(0.3 - 0.4 mg prot.) were incubated at 25° C. in 0.50 ml of the samebuffer containing [³H] pyisamiine (2 nM) and the displacing drugs.

[0163] After 30 min of incubation, 4 ml of ice-cold buffer was added andthe bond and free [³H] pyrilaminie were separated by filtration undervacuum through glass fiber filters (Whatman GF/B). The filters werewashed three times with 4 ml of buffer, dried, placed in 15 ml ofOptifluor, and counted by liquid scintillation spectrometry after a 12 hextraction period.

[0164] All assays were done in triplicate and specific binding wasdefined as the total amount of [³H] pyrilamine bound minus that bound inthe presence of 10⁻⁴M of pyluaxnine. Protein concentration wasdetermined by the Bradford method.

[0165] [³H] pyrilamine, (20 ci/nmol) was obtained from New EnglandNuclear Corp.

[0166] Muscarinic Affinity

[0167] Male Fischer rats (300-350 g) were killed by decapitation andcortexes were rapidly removed and homogenised using a Polytron in 20 vol(w/v) of ice-cold 50 mM PBS buffer (pH 7.4). Homogenates werecentrifuged at 20000× g for 15 min. The precipitated material wasresuspended in assay buffer and was used for binding assay.

[0168] Triplicate incubation tubes contained [³H] QNB (0.16 nM), variousconcentrations of drug and an aliquot of freshly resuspended tissue(˜0.4 mg prot) in a fal volume of 2 ml. Tubes were incubated at 37° C.for 60 min and the incubation was terminated by rapid filtration undervacuum through GF/B glass fiber filters. The filters were rinsed threetimes with ice-cold buffer using a Brandel filtration apparatus(Gaithersburg, Md., USA) and were placed in vials containing 15 ml ofOptifluor ®, cooled overnight, and counted in a liquid scintillation.Specific binding was defined as the excess over blanks containing 1 μMAtropine.

[0169] [³H] QNB 42 ci/nmole was obtained from New England Nuclear Corp.

[0170] Calculations

[0171] Drugs were tested in triplicate at different concentrations, from10⁻⁵ to 10⁻¹⁰ M. IC₅₀'s, the concentration of drug that caused 50%inhibition of [³H]Ligand binding, was obtained using “Allfit” programrunning on an IBM personal computer.

IN VIVO TEST

[0172] Antagonism of Apomorphine-induced climbing in mouse

[0173] Groups of ten mice (CD1 male) were dosed with test compounds bythe subcutaneous route 30 jutes before apomorphine and placedindividually into cylindical wire mesh cages (height 14 cm, diameter 12cm, mesh size 2 mm). Climbing behaviour was assessed at 5 min intervalsfor 30 min, is starting 5 min after apomorphine (1.3 mg/Kg, s.c.) (GregC. Figdon et al. Neuropsychopharmacology Vol. 15,.pp231-242 (1996)).

[0174] Antaionism of 5-MeO-DMT-induced Head Twitches in mouse

[0175] Groups of ten mice of the CD1 strain (male) were utilised toevaluate head twitches induced by 5 methoxy-N,N-dimethyl-tryptamine(5-MeO-DMT) at a subcutaneous dosage of 10 mg/Kg,

[0176] The evaluations were begun 6 minutes from the 5-MeO-DMT andlasted 15 minutes (counting the numxiber of head-twitches produced bythe animal). The substances were administered subcutaneously 30 minutesbefore the 5-MeO-DMT (Greg C. Rigdon et al. Neuropsychopharmacology Vol.15,.pp231-242 (1996)).

[0177] Extrapyramidal Symptom

[0178] The test was performed on male Wistar rats (7-8 animals pergroup); the catalepsy evaluation was carried out by means of a metallicbar 0.6 cm in diameter positioned 10 cm from the workplace. Thesubstances under study were administered subcutaneously 30 minutesbefore the first evaluation. The subsequent observations were recordedat 60, 90, 120, 1807 240, 300 minutes from administration.

[0179] The test consisted in positioning the animal with its forepaws onthe bar and training how long the animal remained hanging onto the baremploying an end-point of 60 seconds (N. A. Moore et al. Journal ofPharmacology and Experimental Therapeutics Vol. 262 pp 545-551 (1992).

RESULTS AND DISCUSSION

[0180] D₁, D₂,D₃ and 5HT_(2a) affinity

[0181] Table 1 reports the averages and standard errors in the affinityvalues expressed as Ki (nM) reported by each product under study withregard to the SHT₂, D₂, D₁ and D₃ receptors.

[0182] These values were compared with the ones relative to referencecompounds which are structurally similar to the compounds of the presentinvention (RS-Octoclothepin, R-(−) Octoclothepin; S-(+)-Octoclothepin)or belonging to the pharmacological class of the atypical antipsychotic(Olanzapine and Clozapine). TABLE 1 Compounds 5HT_(2A) D₁ D₂ D₃Clozapine 11.00 ± 1.00  353.00 ± 35    250.00 ± 57    312.80 ± 65.07 Olanzapine 12.00 ± 1.00  85.00 ± 3.5  69.00 ± 17   25.80 ± 7.75 RS-Octoclothepin 0.22 ± 0.02 2.28 ± 0.15 0.36 ± 0.07 2.38 ± 0.37R-(−)-Octoclothepin 0.16 ± 0.01 2.02 ± 0.17 3.64 ± 0.46 20.90 ± 4.35 S-(+)-Octoclothepin 0.14 ± 0.01 1.97 ± 0.53 0.40 ± 0.04 0.75 ± 0.12(±)-3a 7.85 ± 2.2  160 ± 77  70 ± 17  57 ± 6.2 ST1455 1.14 ± 0.12 27.00± 10   3.80 ± 0.5  ST1460 1.48 ± 0.20 16.40 ± 1.0  49.60 ± 6.0  ST14611.72 ± 0.25 22.00 ± 1.3  2.06 ± 0.2  ST1456  5.1 ± 0.40 78.00 ± 8.76 37.50 ± 3.01  12.20 ± 3.65  Haloperidol 164.10 ± 23.6  318.30 ± 59.2 4.81 ± 1.0  15.4 ± 3.23 Methysergide 5.3 ± 0.8 (−)-cis-Flupentixol 37.8± 1.7  Sulpiride 240 ± 58 Dopamine  11 ± 3.4

[0183] The binding evaluations relative to the compound (±)-3a, to thechloro derivative ST1455 and to the fluoro derivative ST1456, show thatthe substitution in position 7 with a halogen is an important conditionfor improving the affinities of the formula (1) compounds towards the5HT_(2A) D₂ and D₃ receptors.

[0184] Relative to receptor 5-HT_(2A the) 7-chloro derivatives, raceme(ST 1455) and single isomers (form (+) ST1460, form (−) ST 1461)demonstrate an affinity that improves, by virtue of substitution withhalogen, and proves moderately lower than the one shown by thestructurally analogous reference compounds (RS-Octoclothepin,R-(−)-Octoclothepin, S-(+)-Octoclothepin) and greater to that shown bythe atypical neuroleptics Clozapine and Olanzapine.

[0185] The enantiomers of the ST 1455 chloro-derivative, like those ofRS-Octoclothepin, do not present significant differences of affinitytowards the 5HT_(2a) receptor, but reveal a marked stereoselectivity ofaction regarding the capacity of interaction towards the doparinergic D₂receptor.

[0186] While it is observed that R-(−)-Octoclothepin shows approximately10 times less affinity with regard to the D₂ receptor with respect toisoform(+), the preferred compound ST 1460, shows approximately 25 timesless affinity than the (−) isomer, ST 1461.

[0187] It is therefore interesting to note that the preferred product ST1460 presents a lower activity on the D₂ receptors (involved in theextraphyramidal effects), as compared to what its closest structuralanalogue R-(−)-Octoclothepin shows, together with an improved affinityfor the 5HT₂ and D₁ receptors (involved in the neuroleptic action), ascompared to what the reference atypical antipsychotic Olansapiniedemonstrates.

[0188] In the case of the preferred product ST 1460, it is thereforepossible to obtain therapeutic effects associated with a control ofextrapyramidal symptoms using lower doses with respect to thosenecessary for Clozapine or Olanzapine

[0189] Concerning the racemic 7-fluoro derivative, ST 1456, for whichhas been shown an interaction capacity towards the D₂ receptor evenbelow that shown by the best Octoclothepin enantiomer and towards thatshown by Olanzapine, it is believed that it could possess astereoselectivity of interaction towards the very same receptor,analogously to the racemic chloro-derivative.

[0190] Table 2 shows the inhibition constants (pKi) of the formula (I)compounds and of the reference compounds towards the D₁, D₂ D₃ and 5HT₂receptors, and the following ratios of relative affinity D₁/D₂ and5HT₂/D₂ . This last value, if above 1.12, is considered a validindication for describing the “atypical” profile of an antipsychotic(Meltzer et al. J. Pharmacol Exp. Ther 251 (1) pp 238-245 1989).

[0191] Also reported is the LogY parameter which, considering therelative affinities towards the 5HT₂, D₂, and D₁ receptors of eachproduct identifies and distinguishes a classic antipsychotic (LogY>6.48) from an atypical one (Log Y<6.48) (Meltzer et al J. PharmacolExp. Ther 251 (1) pp 238-245 1989). TABLE 2 D₁ D₂ D₁/ Log Compound pKipKi 5HT_(2A)pKi D₂ 5HT₂/D₂ Y Clozapine 6.45 6.60 7.96 0.98 1.21 3.95Olanzapine 7.07 7.16 7.92 0.99 1.11 5.43 RS-Octoclothepin 8.64 9.44 9.660.92 1.02 8.02 R-(−)-Octoclothepin 8.69 8.44 9.80 1.03 1.16 5.37S-(+)-Octoclothepin 8.71 9.40 9.85 0.93 1.05 7.66 (±)-3a 6.8  7.15 8.1 0.95 1.13 4.99 ST1455 7.57 8.42 8.94 0.90 1.06 6.56 ST1460 7.79 7.308.83 1.07 1.21 4.67 ST1461 7.66 8.69 8.76 0.88 1.01 7.40 ST1456 7.117.43 8.29 0.96 1.12 5.39 Haloperidol 6.50 8.32 6.78 0.78 0.82 9.14

[0192] Observation of these results suggests that the preferred compoundST 1460 is superior to its closest structural analogue (−)-Octoclothepin(respectively 1.21 and 1.16) and different from its owning racemic formST1455 and from the isoform(−) ST 1461, for which the above-mentionedparameters describe a profile of classic antipsychotic.

[0193] Concerning a comparison with compounds having a known atypicalantipsychotic activity, the relative affinity ratio 5-HT₂/D₂ and theLogY value of the preferred compound ST 1460 describe a atypical profilecomparable to that of clozapine and superior to olanzapine.

[0194] The raceme fluoro derivative ST 1456 is, unlike the racemicchloro derivative ST1455, an atypical antipsychotic comparable to thereference compound Olanzapine.

[0195] Another interesting aspect of some formula (I) compounds thatemerges from an examination of the parameters represented in Table 3 isthe high value of the D₃/D₁ receptonal affinity ratio they showed. TABLE3 Compound D₁ pKi D₃ pKi D₃/D₁ Clozapine 6.45 6.50 1.01 Olanzapine 7.077.59 1.07 RS-Octoclothepin 8.64 8.62 1.00 R-(−)-Octoclothepin 8.69 7.680.88 S-(+)-Octoclothepin 8.71 9.12 1.05 (±)-3a 6.8  7.24 1.07 ST14567.11 7.91 1.11 Haloperidol 6.50 7.81 1.20

[0196] Said value is, for everyone, comparable to that determined forthe reference compound Olanzapine.

[0197] Moreover, the D₃/D₁ value reported by formula (I) compoundsclearly distinguishes them from the partially atypical neurolepticR-(−)-Octoclothepin which shows an 0.88 activity ratio.

[0198] The relatively greater D₃/D₁ ratio renders formula (I) productsuseful in the treatment of the negative symptoms of schizophrenia whichinvolve the emotional and cognitive sphere, such as for exampledementia, with respect to Octoclothepin, which with its more active D₁receptor is oriented towards the control of symptoms linked to muscletone.

[0199] Affinity relative to the H1 receptors of histamine andmuescarinics.

[0200] Table 4 reports the average and standard deviations of threedeterminations which describe the interaction capacity (Ki, nM) of eachformula (I) and reference compound towards the H₁ receptor of Histamineand towards the muscarinic receptors. TABLE 4 Muscarinic H₁ ReceptorReceptors Compound Ki (nM) E.S. Ki (nM) E.S. Clozapine 14.00 0.00 54.500.00 Olanzapine 0.35 0.20 22.10 13.12 RS-Octoclothepin 1.00 0.08 434.1031.70 R-(−)-Octoclothepin 2.32 0.06 154.60 12.70 S-(+)-Octoclothepin0.62 0.07 748.60 87.30 ST1455 9.46 1.98 418.20 47.65 ST1460 21.33 12.00286.40 13.20 ST1461 1.40 0.06 514.50 154.10 ST1456 7.33 1.36 2224.00105.60 Haloperidol 384.00 0.00 Pyrilamine 12.20 0.09 Atropine 2.59 0.01

[0201] A study of the mentioned parameters shows that the interactioncapacity of the preferred compound ST 1460 towards the H₁ receptor andtowards the muscairtic receptors is less marked than that shown by itsdirect structural analog, the partially atypical neurolepticR-(−)-Octoclothepin, and by the reference compounds of thepharmacological class of the atypical antipsychotic, Clozapine andOlanzapine.

[0202] These results render the compound ST 1460 particularly useful inthe treatment of schizophrenia and distinguish it from the atypicalreference compounds which, by virtue of their greater interactioncapacity towards the above-mentioned receptors, associate antipsychoticefficacy with the appearance of the following side effects: dryness ofthe throat and the respiratory tract, constipation and weight gain.TABLE 5 Dosage that determines approximately 50% climbing inhibitioninduced by apomorphine in the mouse Molecule DOSE (MG/KG) DOSE(μMOLES/KG) Olanzapine 0.12 0.38 Octoclothepin RS 0.02 0.043Octoclothepin R 0.013 0.026 Octoclothepin S 0.041 0.083 ST 1468 0.0520.13 ST 1469 0.10 0.24 ST 1470 0.025 0.06

[0203] TABLE 6 Dosage that determines 50% of the Head-twitchinginhibition induced by 5-MeO-DMT in the mouse Molecule DOSE (MG/KG) DOSE(μMOLES/KG) Olanzapine 0.18 0.58 Octoclothepin RS 0.064 0.14Octoclothepin R 0.089 0.18 Octoclothepin S 0.079 0.16 ST 1468 0.19 0.47ST 1469 0.196 0.49 ST 1470 0.10 0.24

[0204] TABLE 7 Dosage that determines 100% of catalepsy in rats TIME INMINUTES OF INSURGENCE OF CATALEPSY IN DOSE DOSE 100% OF THE MOLECULE(MG/KG) (μMOLES/KG) ANIMALS RS-Octoclothepin 0.6 1.3 120R-(−)-Octoclothepin 14.85 30 120 S-(+)-Octoclothepin 0.3 0.55 300 ST1468 1.22 3 180 ST 1469 >12.2 >30 ST 1470 4.06 10 90

[0205] Table 5 shows the calculated dosage of each single compound thatdetermines a 50% inhibition to climbing behavior induced by apomorphinein the mouse, an indication of a dopaminergic activity.

[0206] From the results a reduction of the arty bond which leads to anincrease in dosage by the compound under study (ST 1469) can be observedboth in vivo as in vitro, in that 0.1 mg/Kg (0.24 μmoles/Kg) arenecessary in order to have an antagonism to the effect produced bystimulation of the dopaminergic system, of approximately 50% withrespect to R-(−)-Octoclothepin whose dosage is much lower at 0.013 mg/Kg(0.026 μmoles/Kg), an indication of R-(−)-Octoclothepin's greateraffinity bond.

[0207] A lesser affinity to the system classifies it as an AtypicalAntipsychotic and makes it comparable to the class of drugs representedby olanzapine.

[0208] Stimulation of the serotoniergic system (table 6) by means of anon-selective agonist of serotomin receptors (5-MeO-DMT) places thecompound (ST 1469) in the in vivo studies comparable to Olanzapine (0.19mg/Kg as opposed to 0.18 mg/Kg) and with less affinity to theserotoninergic system with respect to R-(−)-Octoclothepin (0.089 mg/Kg).

[0209] The onset of the extrapyramidal syndrome (catalepsy), a negativeeffect of the typical neuroleptics, (see table 7) which effect should belacking in those that are atypical, favours ST 1469 in that at a dosagecorresponding to 30 μmoles/Kg R-(−)-Octoclothepin causes catalepsy inall animals after 120 minutes of treatment while the compound understudy does niot present catalepsy throughout the entire observationperiod.

[0210] From the in vivo results produced it can be concluded that ST1469, as characterized by its demonstrated activity on theneurotransmitting systems examined and no insurgence of catalepsy, canbe placed in the atypical neuroleptic class of drugs.

1. Compounds, in racemic form or as isolated optical isomers, having formula (I):

where: R=H, Cl, Br, F, I, C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₁-C₄ alkyl, C₅-C₆ cycloalkyl; R₁=dialkylamine, 4-alyl-1-piperazinyl, 4-hydroxyalkyl-1-piperanyl, 1-imidazolyl, 4-alkyl-1-piperidinyl R₂=hydrogen, C₁-C₄ alkoxy, C₁-C₄ alkylthio and the pharmaceutically acceptable salts thereof.
 2. Compounds according to claim 1, where R represents chlorine or hydrogen, R₁ a 4-methyl-1-piperazinyl group; said R₂ hydrogen.
 3. Compounds according to claim 1, where R represents fluorine, bromine or hydrogen, R₁ a 4-methyl-1-piperaiznyl group; and R₂ hydrogen.
 4. (±)-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiaze-pine.
 5. (±)-7-chloro-9-(4-methylpiperazin-1-yl) -9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine.
 6. (±) -7-chloro-9-(4-methylpiperazin-1-yl) -9,10-dihydropyrrolo [2,1-b][1,3]benzothiazepine.
 7. (±)-7-fluoro-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine.
 8. (±)-7-fluoro-9-(4-ethylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine.
 9. (±)-7-fluoro-9-(4-hyroxyethylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine.
 10. (±)-7-Bromo-9-(4-methylpiperazin-1-yl)-9,10-dihydropyrrolo[2,1-b][1,3]benzothiazepine.
 11. Process for the preparation of the compounds of claims 1-10 comprising the cyclisationl reaction of a derivative containing a phenyl group and a pyrrole group, and where the cyclisation leads to the formation of a 1,3 thiazepine ring.
 12. Process according to claim 11, where the result of said cyclisation reaction is a pyrrolobenzothiazepinone, which is transformed into a formula (I) derivative by substituting the keto group on the thiazepine ring with a group selected from the foregoing definitions of the radical R₁.
 13. Process according to claim 11, where said derivative containing a phenyl group and a pyrrole group is a 1-[2-(methylsulphinyl)phenyl]-2-(pyrrol-1-yl)ethanone, and the cyclisation reaction is carried out in the presence of trifluoracetic anhydride and dimethylformamide.
 14. Process according to claim 11, where said derivative containing a phenyl group and a pyrrole group is an alkyl ester of 2-(phenylthio)pyrrolo-1-selenoacetic acid and the cyclisation reaction is carried out in the presence of a crystalline complex of triflate copper(I) and benzene.
 15. Process for the resolution of racemic compounds of claims 1-10 into the corresponding optically active isomers, by means of fractionated crystallisation of the diastereoisomeric salts obtained by salification with an optically active acid.
 16. Compounds of claims 1-10 for use in therapy in racemic form or as single isolated optical isomers.
 17. Pharmaceutical composition comprising, in racemic form or as single isolated optical isomers, at least a compound of claims 1-10 in combination with pharmaceutically acceptable excipients and/or vehicles, and optionally with other active ingredients which are useful in the treatment of psychoses.
 18. Pharmaceutical composition according to claim 17, in solid or liquid form.
 19. Use of the compounds of claims 1-10, in racemic form or as single isolated optical isomers, in the preparation of an antipsychotic medicinal agent for the treatment and prevention of psychoses.
 20. Use according to claim 19, where said psychosis takes the form of schizophrenia, paranoid states, manic-depressive states, affective disorders, social withdrawal, personality regression, or hallucinations.
 21. Use according to claim 19, in particular of the compounds of claim 1, wherein R is hydrogen, fluorine, bromine, for the treatment of the negative symptoms of schizophrenia involving the emotional and cognitive spheres.
 22. Use according to claim 21, where said negative symptom takes the form of dementia. 